TW588047B - Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions - Google Patents

Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions Download PDF

Info

Publication number
TW588047B
TW588047B TW087102265A TW87102265A TW588047B TW 588047 B TW588047 B TW 588047B TW 087102265 A TW087102265 A TW 087102265A TW 87102265 A TW87102265 A TW 87102265A TW 588047 B TW588047 B TW 588047B
Authority
TW
Taiwan
Prior art keywords
group
patent application
methyl
scope
general formula
Prior art date
Application number
TW087102265A
Other languages
Chinese (zh)
Inventor
Norbert Hauel
Uwe Ries
Henning Priepke
Wolfgang Wienen
Jean Marie Stassen
Original Assignee
Boehringer Ingelheim Pharma
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26034058&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=TW588047(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from DE19706229A external-priority patent/DE19706229A1/en
Priority claimed from DE1997151939 external-priority patent/DE19751939A1/en
Application filed by Boehringer Ingelheim Pharma filed Critical Boehringer Ingelheim Pharma
Application granted granted Critical
Publication of TW588047B publication Critical patent/TW588047B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/74—Sulfur atoms substituted by carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to new disubstituted bicyclic heterocycles of general formula (I): Ra-A-Het-B-Ar-E, wherein A, B, Ar, Het and Ra are defined as in claim 1, the tautomers, stereoisomers and mixtures thereof and the salts thereof which have valuable properties. Thus, the compounds of the above general formula I, wherein E denotes a cyano group, are valuable intermediates for preparing the other compounds of general formula I, and the compounds of the above general formula I, wherein E denotes an RbNH-C(=NH)- group, have valuable pharmacological properties, particularly a thrombin-inhibiting effect and the effect of prolonging thrombin time.

Description

588047 A8 B8 C8 D8 六、申請專利範圍 轰基’苄基氧基羰基，苯甲酸基，p-Cy燒基苯甲 酿基或菸醯基，同時上述（：卜9_烷氧基羰基上2-位的 乙氧基可又以烷基磺醯基或·3_烷氧基）_乙 基取代的， A r指1，4 ·伸苯基，其未經或經氯原子或以甲基，乙 基’或甲氧基取代，或指2，5 -伸。塞吩基，588047 A8 B8 C8 D8 VI. Scope of patent application: 'benzyloxycarbonyl, benzoate, p-Cy alkyl, benzyl or nicotinyl, and at the same time (: Bu 9_alkoxycarbonyl on 2 The ethoxy group at the-position may be further substituted with an alkylsulfonyl group or a 3-alkoxy) -ethyl group, and A r refers to a 1,4-phenylene group, which is not or via a chlorine atom or a methyl group. , Ethyl 'or methoxy substituted, or 2,5-extend. Sephenyl,

Het指1-甲基-2,5-苯并伸咪唑基，1 -環丙基-2,5-苯并伸 咪峻基’ 2,5_苯并伸噻唑基，丨-甲基-2,5-伸啕哚基，l 甲基-2,5-咪唑并[4,5-b]伸吡啶基，3-甲基-2,7-咪唑并 [l，2-a]伸吡啶基或丨_甲基-2,5-噻吩并[2,3-d]伸咪唑基， 及 R a指R2NR3-基團，其中 以2是c i·3·烷基（其可以羧基取代），c 1β6-烷基氧基羰 基’苄基氧基羰基，甲基磺醯基胺基羰基，或1Η-四 唑-5 -基， 以藉基取代的(：2_3·烷基，芊基氧基，羧基-Cl-3-烷基 胺基，Cw烷氧基羰基_Ci_3-烷基胺基，n_(Ci3-烷 基）-羧基-C丨烷基胺基或N-(C w烷基）-C ^烷氧 基羰基-C丨·3·烷基胺基，在上述基團中於鄰近氮原子 的α -位的碳原子可以是未經取代的，及 R3指玦丙基，其中不飽和的部分可不直接聯於R2NR3 基團的氮原子上，未經或經氟或氯原子或甲基或甲 氧基取代的苯基，或指吡啶基， 其互變異構物及其鹽。 -3- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐).Het refers to 1-methyl-2,5-benzidimidazolyl, 1-cyclopropyl-2,5-benzidimidazolyl '2,5_benzylthiazolyl, 丨 -methyl-2 , 5-xenopyridyl, lmethyl-2,5-imidazo [4,5-b] pyridyl, 3-methyl-2,7-imidazo [l, 2-a] pyridyl Or 丨 _methyl-2,5-thieno [2,3-d] imidazolyl, and Ra refers to the R2NR3- group, where 2 is ci · 3 · alkyl (which may be substituted by carboxyl), c 1β6-alkyloxycarbonyl 'benzyloxycarbonyl, methylsulfonylaminocarbonyl, or 1'-tetrazol-5-yl, substituted with a borrowing group (: 2-3-alkyl, fluorenyloxy, Carboxy-Cl-3-alkylamino, Cw alkoxycarbonyl_Ci_3-alkylamino, n_ (Ci3-alkyl) -carboxy-C 丨 alkylamino or N- (Cw alkyl)- C ^ alkoxycarbonyl-C3 ·· 3 · alkylamino, the carbon atom at the α-position adjacent to the nitrogen atom in the above-mentioned group may be unsubstituted, and R3 refers to propyl, where unsaturated The part may not be directly connected to the nitrogen atom of the R2NR3 group, a phenyl group which is not or substituted with a fluorine or chlorine atom or a methyl group or a methoxy group, or a pyridyl group, a tautomer thereof, and a salt thereof. -3 -This paper is of suitable size Use Chinese National Standard (CNS) A4 specification (210X297 mm).

、申請專利範圍 3.根據申請專利範圍第1項之通式I二取代雙環雜環，其中 A指聯於H e t基團上的苯或噻吩部分上的羰基， B指伸乙基，其中聯於a r基團上的亞甲基可係經-NRi基 團取代的，其中2. Patent application scope 3. Disubstituted bicyclic heterocyclic ring of general formula I according to item 1 of the patent application scope, wherein A refers to the carbonyl group on the benzene or thiophene moiety attached to the Het group, and B refers to the ethyl group, where the The methylene group on the ar group may be substituted with a -NRi group, where

Ri指氫原子或甲基， E指RbNH-C(=NH)-基團，其中Ri refers to a hydrogen atom or a methyl group, and E refers to an RbNH-C (= NH)-group, where

Rb指氫原子，羥基，Crr烷氧基羰基，環己基氧基 羰基，芊基菸氧基羰基，苯甲醯基，p-C ^3-烷基苯 甲醯基或菸醯基，同時上述Ci-9-烷氧基羰基上2-位 的乙氧基可以是又以曱基磺醯基或2 -乙氧基乙基取 代的， A r指1，4 -伸苯基，其未經或經甲氧基取代，或指2，5-伸屬吩基，Rb means a hydrogen atom, a hydroxyl group, a Crr alkoxycarbonyl group, a cyclohexyloxycarbonyl group, a fluorenyl nicotinyloxycarbonyl group, a benzamyl group, a pC ^ 3-alkylbenzyl group or a nicotinyl group, and the above Ci- The ethoxy group at the 2-position on the 9-alkoxycarbonyl group may be substituted with a fluorenylsulfonyl group or a 2-ethoxyethyl group. A r means 1,4-phenylene group, which is not Methoxy substituted, or 2,5-phenylene,

Het指1-甲基-2,5-苯并伸咪唑基，2,5·苯并伸噻唑基， 1-甲基-2,5-伸吲哚基，或1-曱基-2,5-嘍吩并[2,3-(1]伸 咪峻基，及 RJR2NR3-基團，其中 R2是以羧基取代的（：10-烷基，C!_6-烷基氧基羰基， 芊基氧基羰基，甲基磺醯基胺基羰基，或ΙΗ-四唑-5-基， 以羥基取代的C2_3-烷基，苄基氧基，羧基CN3-烷基 胺基’ Ci-3_说氧基談基- Ci-3-坑基胺基’N - ( C 1 _ 3 燒 基）-羧基-c 1-3-烷基胺基或N-(C 1β3·烷基）-C w烷氧 基羰基-C卜3-烷基胺基，在上述基團中於鄰近氮原子 588047 A8 B8 C8 D8 申請專利範園 的α -位的碳原子可以是未經取代的，及 R 3指經或未經氟原子取代的+基或和2 - ρ比唉基， 其' 互變異構物及其鹽。 4·根據申請專利範圍第1項之通式1二取代雙環雜環，其係 選自下列化合物： (a) 2-[N-(4-脒基苯基胺基甲基]•苯并p塞峻-5-幾 酸-N-苯基-N-(2-羧基乙基）-醯胺， (b) 2-[N-(4-脒基苯基）-N-甲基-胺基甲基]•苯并嚷 峻-5-基·幾酸-N-苯基-N-(2-每基談基乙基）-酸胺， U) 1-甲基-2·[Ν-(4-脒基苯基）-胺基甲基]-苯并味 唑-5 -基-羧酸-Ν-苯基-Ν-(2-羥基羰基乙基）·醯胺， (d) 1 -甲基-2- [Ν-(4·脒基苯基）-胺基甲基]-苯并味 唆-5-基-羧酸-Ν-苯基-Ν-(3-羥基羰基丙基）-醯胺， U) 1 -甲基- 2-[Ν-(4_脒基苯基）-胺基甲基]-苯幷味 嗤_5 -基-羧酸-Ν-(2·吡啶基）-Ν-(羥基碳基甲基μ酿 胺， (f) 1 -甲基- 2-[2-(2-脒基苯硫-5 -基）-乙基]-苯并味 唑·5-基-羧酸·Ν-(2-吡啶基）-Ν·(2-羥基羰基乙基）_酸 胺， (g) 1-甲基-2-[N-(4-脒基苯基）·胺基甲基]-苯并味 咬-5-基羧酸-N-(2-吡啶基）·Ν-(2-羥基羰基乙基μ酿 胺， (h) 1 -曱基- 2-[2·(4-脒基苯基）乙基]-苯并咪唑_5_ 基羧酸-Ν-(2-吡啶基）-Ν-(2·羥基羰基乙基）_醯胺， -5- 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐）. ' -^ 588047 έβ C8 D8 六、申請專利範圍 (i) 1 -甲基- 2-[2-(4·脒基苯基）乙基]-苯并咪唑- 5· 基-羧酸-Ν-苯基-Ν-( 2 -·經基羰基乙基）-醯胺， (j) 1 -甲基- 2-[2-(4-脒基苯基）乙基]-苯并咪唑- 5-基-羧酸-N-苯基-Ν-[2-(1Η-四唑-5-基）乙基]-醯胺， (k) 1 -甲基- 2-[N-(4-脒基苯基）-胺基曱基]-苯并咪 唑-5-基羧酸-N-苯基-Ν-[2-(1Η-四唑-5-基）乙基]-醯 胺， (l) 1-甲基-2-[N-(4-脒基苯基）-N-甲基-胺基甲基]-苯并咪唑-5 -基-羧酸-N-(2-吡啶基）-N-(2 -羥基羰基乙 基）-醯胺， (m) 1-甲基_2-[N-(4-脒基苯基）-Ν·甲基-胺基甲基]-苯并咪唑-5 -基-羧酸-Ν-(3-吡啶基）-N-(2-羥基羰基乙 基）-醯胺， (η) 1-甲基-2-[Ν-(4·脒基苯基）_Ν -甲基-胺基甲基卜 苯并咪唑5 -基-羧酸苯基-Ν-(2-羥基羰基乙基）-醯 胺， (ο) 1 -甲基- 2-[Ν-(4-脒基苯基）-胺基甲基]-苯并咪 唑-5-基羧酸苯基-Ν-[(Ν-羥基羰基乙基-Ν-甲基）-2 -胺基乙基]-酿胺， (ρ) 1 -甲基- 2-[Ν-(4-脒基苯基）-胺基甲基]-苯并咪 唑-5-基-羧酸-Ν-(3 -氟苯基）-Ν-(2-羥基羰基乙基）-醯 胺， (q) 1 -甲基- 2-[N-(4-脒基苯基）-胺基甲基]-苯并咪 唑-5 -基-羧酸-N- (4·氟苯基）-N - ( 2 -羥基羰基乙基）-醯 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 588047 A8 B8 C8Het refers to 1-methyl-2,5-benzimidazolyl, 2,5 · benzothiazolyl, 1-methyl-2,5-indole, or 1-fluorenyl-2,5 -Fluoreno [2,3- (1] endimyl, and RJR2NR3- groups, where R2 is substituted with a carboxyl group (: 10-alkyl, C! _6-alkyloxycarbonyl, fluorenyloxy Carbonyl, methylsulfonylaminocarbonyl, or 1-tetrazol-5-yl, C2-3-alkyl substituted with hydroxyl, benzyloxy, carboxyl CN3-alkylamino Alkyl-Ci-3-pitylamino'N-(C 1 _ 3 alkyl) -carboxy-c 1-3-alkylamino or N- (C 1β3 · alkyl) -C w alkoxy Carbonyl group-C and 3-alkylamino group, in the above group, the carbon atom at the α-position adjacent to the nitrogen atom 588047 A8 B8 C8 D8 may be unsubstituted, and R 3 means The unsubstituted fluorine group or the + group and the 2-p ratio group, its' tautomers and salts thereof. 4. Disubstituted bicyclic heterocyclic ring according to the general formula 1 of the first patent application scope, which is selected from The following compounds: (a) 2- [N- (4-fluorenylphenylaminomethyl) • benzo-p-sechon-5-chinic acid-N-phenyl-N- (2-carboxyethyl)- Fluorenamine, (b) 2- [N- (4-fluorenylphenyl) ) -N-methyl-aminomethyl] • benzopyrene-5-yl · chinoic acid-N-phenyl-N- (2-perylethyl) -acid amine, U) 1- Methyl-2 [[N- (4-fluorenylphenyl) -aminomethyl] -benzotriazole-5 -yl-carboxylic acid-N-phenyl-N- (2-hydroxycarbonylethyl) · Fluorenamine, (d) 1 -methyl-2- [N- (4 · fluorenylphenyl) -aminomethyl] -benzoisofluoren-5-yl-carboxylic acid-N-phenyl-N -(3-hydroxycarbonylpropyl) -fluorenamine, U) 1 -methyl- 2- [N- (4_fluorenylphenyl) -aminomethyl] -benzenesulfur miso-5 -yl-carboxyl Acid-N- (2.pyridyl) -N- (hydroxycarbylmethylμamine), (f) 1-methyl-2- [2- (2-fluorenylphenylthio-5-yl) -ethyl Yl] -benzimidazole · 5-yl-carboxylic acid · N- (2-pyridyl) -N · (2-hydroxycarbonylethyl) -acid amine, (g) 1-methyl-2- [N -(4-fluorenylphenyl) · aminomethyl] -benzyl-5-ylcarboxylic acid-N- (2-pyridyl) · N- (2-hydroxycarbonylethyl μ amine, ( h) 1-fluorenyl-2- [2 · (4-fluorenylphenyl) ethyl] -benzimidazole-5-ylcarboxylic acid-N- (2-pyridyl) -N- (2 · hydroxycarbonylethyl Base) _amidine, -5- This paper size applies to China National Standard (CNS) Α4 size (210X297 mm). '-^ 588047 έ β C 8 D8 6. Scope of patent application (i) 1-Methyl-2- [2- (4 · fluorenylphenyl) ethyl] -benzimidazole-5 · yl-carboxylic acid-N-phenyl-N- (2-· Ethylcarbonylethyl) -amidamine, (j) 1 -methyl-2- 2- [2- (4-fluorenylphenyl) ethyl] -benzimidazole- 5-yl-carboxylic acid- N-phenyl-N- [2- (1Η-tetrazol-5-yl) ethyl] -fluorenamine, (k) 1-methyl-2- [N- (4-fluorenylphenyl) -amine Fluorenyl] -benzimidazol-5-ylcarboxylic acid-N-phenyl-N- [2- (1fluoren-tetrazol-5-yl) ethyl] -fluorenamine, (l) 1-methyl- 2- [N- (4-fluorenylphenyl) -N-methyl-aminomethyl] -benzimidazole-5 -yl-carboxylic acid-N- (2-pyridyl) -N- (2- Hydroxycarbonylethyl) -fluorenamine, (m) 1-methyl_2- [N- (4-fluorenylphenyl) -N · methyl-aminomethyl] -benzimidazole-5 -yl- Carboxylic acid-N- (3-pyridyl) -N- (2-hydroxycarbonylethyl) -fluorenamine, (η) 1-methyl-2- [N- (4 · fluorenylphenyl) _N-formyl -Amino-methylbenzimidazole 5-yl-carboxylic acid phenyl-N- (2-hydroxycarbonylethyl) -fluorenamine, (ο) 1-methyl-2- [N- (4-fluorene Phenyl) -aminomethyl] -benzimidazol-5-ylcarboxylic acid phenyl-N-[(N-hydroxycarbonylethyl-N-methyl) -2 -aminoethyl] -methylamine , ( p) 1-methyl-2- [N- (4-fluorenylphenyl) -aminomethyl] -benzimidazol-5-yl-carboxylic acid-N- (3-fluorophenyl) -N- (2-hydroxycarbonylethyl) -fluorenamine, (q) 1-methyl- 2- [N- (4-fluorenylphenyl) -aminomethyl] -benzimidazole-5 -yl-carboxylic acid -N- (4-Fluorophenyl) -N-(2 -Hydroxycarbonylethyl) -copies This paper is sized for China National Standard (CNS) A4 (210 X 297 mm) 588047 A8 B8 C8

胺， ^甲基β2-[Ν-(4·脒基甲氧基_苯基）·胺基甲 '"并米坐基-&故苯基-N-( 2 -幾基羰基乙 基）-酸胺， (S) ―1·甲基.2-[N-(4-脒基-2·甲氧基·苯基卜胺基甲 ]笨并米嗅· 5 -基-叛酸-N_ (2-p比咬基）-N - (2 -幾基羰 基乙基）-醯胺， (t)丨-甲基·2-[Ν-(4-脒基苯基）胺基甲基卜吲哚_5_ 基·幾酸苯基_Ν•(八甲氧基羰基乙基）_醯胺，及— U)丨-甲基·ΜΝ-(4-脒基苯基）胺基甲基卜噻吩并 [2,3-d]咪唑_5_基羧酸苯基·ν_(2_羥基羰基乙基 醯胺， 土广 其互變異構物及其鹽。 5.根據申請專利範圍第1.項之通式I二取代雙環雜環，其係 1_甲基-2-[ν_(4-脒基苯基）-胺基甲基μ苯并咪唾_5_ 基酸-Ν-苯基_Ν-(2_羥基羰基乙基）_醯胺，及其 鹽0 6·根據申請專利範圍第1項之通式I二取代雙環雜環，其係 1_甲基-2-[Ν-(4-脒基苯基）-胺基甲基μ苯并咪唑_5_ 基-羧酸-Ν-(2-吡啶基）-Ν-(羥基羰基乙基）-醯胺，及 其鹽。 7.根據申請專利範圍第1項之通式I二取代雙環雜環，其係 1-甲基-2-[Ν-(4-脒基-2 -甲氧基-苯基胺基甲基卜苯 并咪唑-5 -基-羧酸-Ν - ( 2 -吡啶基）-Ν ·( 2 -羥基羰基乙 本紙張尺度適用中國國家標準(CNS) Α4規格(210Χ 297公釐）. 六、申請專利範圍 基）-酸胺，及其鹽。 8. 根據申請專利範圍第1項之通式I二取代雙環雜環，其係 1-甲基-2-[N-(4-(N_正己基氧基羰基脒基卜苯基）胺基 甲基]-苯并咪唑-5-基-羧酸·Ν-(2-吡啶基）-N-(2 -乙氧 基羰基乙基）_酸胺，及其鹽。 9. 根據申請專利範圍第丨至8項中任一項之通式〗二取代雙 %雜％ ’其係生理上可接受的鹽，其中E指RbNH-C(=NH)-基團。 10. 種具有延長凝血酶時間效果、抑制凝血酶效果或對相 關的絲胺酸蛋白酶有抑制效果之醫藥組合物，其包含根 據申請專利範圍第丨至8項中任一項之化合物，其中£指 RbNH-C(=NH)-基團，或根據申請專利範圍第9項之鹽， 其不含或含一或多種惰性載劑及/或稀釋劑。Amine, ^ methyl β2- [N- (4-Methoxymethoxy-phenyl) -aminomethyl '" Mexanyl- & therefore phenyl-N- (2-Ethylcarbonylethyl ) -Acid amine, (S) -1 methyl. 2- [N- (4-fluorenyl-2 · methoxy · phenylbranylmethyl] benzyl ol · 5-yl-renyl acid- N_ (2-p specific sulfanyl) -N-(2-Ethylcarbonylethyl) -fluorenamine, (t) 丨 -methyl · 2- [N- (4-fluorenylphenyl) aminomethyl Oxindole_5_yl_chinophenyl_N • (octylmethoxycarbonylethyl) _amidine, and —U—Methyl · MN— (4-fluorenylphenyl) aminomethyl Buthieno [2,3-d] imidazol-5-ylcarboxylic acid phenyl · ν_ (2-hydroxycarbonylethylamidamine), tautomeric tautomers and salts thereof. 5. According to the scope of patent application No. 1 The general formula I of the item is a disubstituted bicyclic heterocyclic ring, which is 1-methyl-2- [ν_ (4-fluorenylphenyl) -aminomethyl μ benzimidazol-5-N-phenyl _Ν- (2-hydroxycarbonylethyl) _amidine, and its salts 0 6 · Disubstituted bicyclic heterocyclic ring according to the general formula I of the first patent application scope, which is 1-methyl-2- [Ν- (4-fluorenylphenyl) -aminomethyl μ benzimidazol-5-yl-carboxylic acid-N- (2-pyridyl) -N- (hydroxycarbonylethyl) -fluorenamine And its salts. 7. Disubstituted bicyclic heterocyclic ring of general formula I according to item 1 of the scope of patent application, which is 1-methyl-2- [N- (4-fluorenyl-2 -methoxy-phenyl) Aminomethyl benzobenzimidazole-5 -yl-carboxylic acid-N-(2 -pyridyl) -N · (2 -hydroxycarbonylethyl) This paper applies Chinese National Standard (CNS) A4 (210 × 297 mm) ) 6. Range of patent application)-acid amines and salts thereof 8. Disubstituted bicyclic heterocyclic ring according to the general formula I of item 1 of the scope of patent application, which is 1-methyl-2- [N- (4 -(N-n-hexyloxycarbonylamidinophenyl) aminomethyl] -benzimidazol-5-yl-carboxylic acid · N- (2-pyridyl) -N- (2-ethoxycarbonyl Ethyl) _ acid amines, and salts thereof. 9. According to the general formula of any one of claims 1 to 8 of the scope of the application, the di-substituted bis% hetero% 'is a physiologically acceptable salt, where E refers to RbNH -C (= NH)-group. 10. A pharmaceutical composition having the effect of prolonging thrombin time, inhibiting thrombin, or inhibiting related serine proteases, which comprises the first to eighth aspects according to the scope of the patent application A compound according to any one of clauses, wherein £ means RbNH-C (= NH)-group, The salt of the 9 range patent, free, or contain one or more inert carriers and / or diluents.

U·根據申請專利範圍第1至8項中任一項之化合物，其中E 扣RbNH-C(=NH)-基團，或根據申請專利範圍第9項之 鹽，其係用於製備醫藥組合物，此醫藥組合物具有延長 叛血酶時間的效$ ’抑㈣凝血酶效果及對相關的絲胺酸 蛋白酶有抑制效果。 12· —種製備根據申請專利範圍第〗項之化合物及其生理上 可接受的鹽的方法，其特徵在於 a.要製備通式j化合物，其中£指尺以卜基團， 其中Rb是氫原子，羥基*Cl-3_烷基，時 以如下通式之化合物U · A compound according to any one of claims 1 to 8 in the scope of the patent application, wherein E is deducted from the RbNH-C (= NH)-group, or a salt according to the scope of the patent application, which is used to prepare a pharmaceutical composition This pharmaceutical composition has the effect of prolonging the time of rebellase. It has the effect of inhibiting thrombin and inhibiting the related serine protease. 12. · A method for preparing a compound and a physiologically acceptable salt thereof according to item 1 of the scope of the patent application, characterized in that a. A compound of the general formula j is to be prepared, wherein £ refers to a group and Rb is hydrogen Atom, hydroxy * Cl-3_alkyl, in the following formula

Ra - A - Het - B - Ar - C(=NH) . Zl ，⑴） 588047 έ88 C8 ________D8_ 六、申請專利範園 此化合物可在反應混合物中生成的， 其中 A，B，Ar，Het，及113之定義如申請專利範圍第五至7項 所述’及Z 1指烷氧基或芳烷氧基，烷基硫基或芳烷基 硫基， 與如下通式的胺反應 H2N - Rb’ ，（III) 其中 - Rbf指氫原子或藉基或C 烷基，或 b ·要製備通式I化合物，其中Ra_A_基團及e之定義如 申請專利範圍第1至8項所述，先決條件是Ra_A-基團含 有叛基及E之定義如申請專利範圍第1至8項所述，或是 Ra_A-基團之定義如申請專利範圍第1至8項之所述而e 指NH-C(=NH)-基團，.或Ra_A-基團含有羧基而e指NH-C(=NH)-基團，時： 將如下通式之化合物Ra-A-Het-B-Ar-C (= NH). Zl, ⑴) 588047 88 88 C8 ________D8_ VI. Patent application for this compound can be generated in the reaction mixture, of which A, B, Ar, Het, and The definition of 113 is as described in the fifth to seventh items of the scope of the patent application. 'And Z 1 refers to alkoxy or aralkoxy, alkylthio or aralkylthio, and reacts with an amine of the general formula H2N-Rb' (III) where-Rbf refers to a hydrogen atom or a boring group or a C alkyl group, or b. To prepare a compound of the general formula I, wherein the definition of the Ra_A_ group and e is as described in item 1 to 8 of the scope of patent application, subject to prerequisite. Provided that the Ra_A- group contains the terminus and E as defined in item 1 to 8 of the scope of patent application, or the Ra_A- group is as defined in item 1 to 8 of the scope of patent application and e refers to NH- C (= NH)-group, or Ra_A- group contains carboxyl group and e means NH-C (= NH)-group:

Ra丨-A - Het - B - Ar - C - E* ，（IV) 其中 A，B，Ar及Het之定義如申請專利範圍第1至7項所述，Ra 丨 -A-Het-B-Ar-C-E *, (IV) where A, B, Ar and Het are defined as described in items 1 to 7 of the scope of patent application,

Ra - A-基團及E ’之定義如申請專利範圍第1至8項給Ra-A-基團及E所下的定義，先決條件是rj _A-基團含有可 藉水解、酸或鹼處理、熱分解或加氫分解轉化成羧基的 基團，E之定義如申請專利範圍第1至8項所述，或E，指 可藉水解、酸或鹼處理、熱分解或加氫分解轉化成NHr _ -9- ^紙張尺度適用中國國家標準(CNS) A4規格(21〇χ 297公釐）· ------ 588047 Λβ B8 C8 ---— ___D8 六、申請專利範圍 --- c卜NH)-基團的基團，Ra’_冬基團之定義如申請專利範 圍第1至8項給Ra-A-基團所下的定義，或是R:A_基團 §有可藉水解、敗或驗處理、熱分解或加氫分解轉化成 羧基的基團，E’指可藉水解、酸或鹼處理、熱分解或加 氫分解轉化成NH2_C(=NH)-基團的基團， 藉水解、酸或驗處理、熱分解或加氫分解轉化成通式I 化a物’其中Ra_A_基團之定義如申請專利範圍第1至8 項所述，先決條件是Ra_冬基團含有羧基，而E之定義 如申請專利範圍第1至8項所述，或是Ra_A_基團之定義 如申請專利範圍第！至8項所述，而E指nh^c卜nh>基 團’或是Ra-A-基團含有羧基而e指NH2-C(=NH)_基團， 或 c ·要製備通式I化合物，其中Ra_A_基團含申請專利範 圍第1至7項所述Ra-A-基團的一種酯，時 以如下通式化合物The definitions of Ra-A- group and E 'are the same as those defined for Ra-A- group and E in the scope of application for patents Nos. 1 to 8. The prerequisite is that the rj _A- group contains A group converted to a carboxyl group by treatment, thermal decomposition or hydrodecomposition, the definition of E is as described in the scope of claims 1 to 8 of the patent application, or E means that it can be converted by hydrolysis, acid or alkali treatment, thermal decomposition or hydrodecomposition. Cheng NHr _ -9- ^ The paper size is applicable to the Chinese National Standard (CNS) A4 specification (21〇χ 297 mm) · ------ 588047 Λβ B8 C8 ------- ___D8 VI. Application scope --- c NH)-group, the definition of Ra'_ group is as defined for Ra-A- group in item 1 to 8 of the scope of patent application, or R: A_ group has A group that can be converted into a carboxyl group by hydrolysis, degradation or inspection, thermal decomposition or hydrolytic decomposition, E 'refers to a group that can be converted to NH2_C (= NH) -group by hydrolysis, acid or alkali treatment, thermal decomposition or hydrolytic decomposition. Group by hydrolysis, acid or test treatment, thermal decomposition or hydrolytic decomposition into the general formula I a ', where the definition of the Ra_A_ group is as described in the first to eighth scope of the patent application, the prerequisite is Ra _Winter group Contains a carboxyl group, and the definition of E is as described in items 1 to 8 of the scope of patent application, or the definition of Ra_A_ group is as in the scope of patent application! To 8 as described above, and E refers to nh ^ c bnh> group 'or Ra-A- group contains carboxyl group and e refers to NH2-C (= NH) _ group, or c A compound in which the Ra_A_ group contains an ester of the Ra-A- group described in claims 1 to 7 of the scope of patent application, when it is a compound of the following formula

Ra，f - A - Het - B - Ar - Ε ，（λ〇 其中 B ’ E ’ Ar及Het之定義如申請專利範圍第1至8項所述， Ran-A-基團之定義如申請專利範圍第1至8項給Ra_A-所 下的定義，先決條件是基團含有羧基或可用醇轉 化成對應的酯的基團，與下式的醇反應 HO R7 ，（ VI) 其中 R7是如申請專利範圍第1至8項所述可於活體内裂解的 -10· 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱） 588047 A8 B8 C8 D8 申請專利範圍 基團的烷基邵分，但不能用R4-CO-〇_(r5CR6)_基團產生 羧基，或與其甲醯胺乙縮醛反應， 或與如下通式的化合物反應 Z2 _ R8 ，（VII) 其中 R8指申請專利範圍第1至7項所述可於活體内裂解的基 團的fe基部分’但不能用R4-CO-〇-(r5cR6)_基團產生幾 基，及Z 2指離去基，或 d .要製備通式I化合物，其中R b指可於活體内裂解的基 團，時 以如下通式之化合物Ra, f-A-Het-B-Ar-Ε, (λ〇 where B 'E' Ar and Het are defined as described in item 1 to 8 of the scope of patent application, and Ran-A- group is as defined in the patent application The definition of Ra_A- in the first to eighth range, the prerequisite is that the group contains a carboxyl group or a group that can be converted to the corresponding ester with an alcohol, and reacts with the alcohol of the formula HO R7, (VI) where R7 is as applied The range of patents Nos. 1 to 8 can be lysed in vivo -10 · This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 public love) 588047 A8 B8 C8 D8 Shao Fen, but cannot use the R4-CO-〇_ (r5CR6) _ group to generate a carboxyl group, or react with its formamide acetal, or react with a compound of the following formula Z2_R8, (VII) where R8 refers to the application The fe group portion of the group which can be cleaved in vivo as described in the patent scope items 1 to 7 'but cannot use R4-CO-O- (r5cR6) _ group to generate several groups, and Z 2 refers to a leaving group, or d. To prepare a compound of general formula I, in which R b refers to a group that can be cleaved in vivo, a compound of the following formula

Ra - A - Het _ B _ Ar - C(=NH) _ 簡2 ，（ VIII) 其中Ra-A-Het _ B _ Ar-C (= NH) _ Jane 2, (VIII) where

Ra，A，Het，B及A r之定義如申請專利範園第1至7項所 述，與如下通式之化合物反應 z2 - r7 ，（IX) 其中 R 7指可於活體内裂解的基團’ Z2指離核離去基’或 e·要製備通式I化合物，其中B指伸乙基，其中亞曱基 是以亞磺醯基或磺醯基所取代’時 將如下通式之化合物氧化The definitions of Ra, A, Het, B and Ar are as described in items 1 to 7 of the patent application park, and react with compounds of the following formula z2-r7, (IX) where R 7 refers to a group that can be cleaved in vivo. The group 'Z2 refers to a leaving group' or e. To prepare a compound of the general formula I, where B is an ethylidene group, in which the fluorenylene group is substituted by a sulfinyl group or a sulfonyl group, the formula will be as follows: Compound oxidation

Ra - A - Het - Bf - Ar - E ，（X) 其中 A，E，Ar，Het及R a之定義如申請專利範圍第1至7項所 -11- 588047Ra-A-Het-Bf-Ar-E, (X) where A, E, Ar, Het and R a are defined as in the scope of patent applications Nos. 1 to -11 588047

六、申請專利範園 述，及 B，指伸乙基’其中亞甲基是以亞續酸基或績醢基所取 代，或 f.要製備通式1之化合物’其中E是氰基，B是伸乙 基，其中聯於H e t或A Γ上的亞甲基係由氧或硫原子，或 由亞磺醯基’磺醯基’談基或-NR「基團所取代，時 用如下通式之化合物6. Patent application, and B, refers to the ethyl group 'wherein the methylene group is substituted with a carboxylic acid group or a methyl group, or f. To prepare a compound of the general formula 1' where E is a cyano group, B is an ethyl group, in which the methylene group linked to He or A Γ is substituted by an oxygen or sulfur atom, or by a sulfinyl'sulfonyl group or -NR "group. Compounds of the following formula

Ra A - Het - U ，（XI) 與如下通式之化合物反應 V - Ar - CN > (XII) 其中Ra A-Het-U, (XI) reacts with a compound of the formula V-Ar-CN > (XII) where

Ra，A，Ar及Het之定義如申請專利範圍第1至8項所 述， U或 V基團之一是 HO-，HS_，HOSO-，H0S02-或 HNRr 基團，另一基團是Z3CH2_，其中Ri之定義如申請專利 範圍第1至8項所述，Z3是離核離去基，或 g·要製備通式I之化合物’其中E是氰基，RjR2NR3_ 基團，時 用如下通式之化合物 Η - A - Het - B - Ar - CN ，（XIII) 其中 A，B，H e t及A r之定義如申請專利範圍第i至8項所 述，與如下通式之胺反應 •12- 588047The definitions of Ra, A, Ar and Het are as described in item 1 to 8 of the scope of patent application. One of the U or V groups is HO-, HS_, HOSO-, H0S02- or HNRr group, and the other group is Z3CH2_ Where the definition of Ri is as described in items 1 to 8 of the scope of the patent application, Z3 is a leaving group, or g. To prepare a compound of general formula I, where E is a cyano group and RjR2NR3_ group, use the following formula: The compound of formula Η-A-Het-B-Ar-CN, (XIII) where A, B, Het and Ar are defined as described in item i to 8 of the scope of patent application, and reacted with an amine of the following formula: 12- 588047

8 8 8 8 A BCD8 8 8 8 A BCD

六、申請專利範園Application for Patent Park

R Η — N: ，（XIV)R Η — N: (XIV)

R 其中 R2及R3之定義如申請專利範圍第1至8項所述’或與其 可反應的衍生物反應，或 h·要製備通式I之苯并咪唑基，苯并嘧唑基或苯并％唑 基化合物’其中B是伸乙基，時 以如下通式化合物 ,(XV) -crR wherein R2 and R3 are defined as described in Items 1 to 8 of the scope of the patent application, or react with a reactive derivative thereof, or h. To prepare a benzimidazolyl, benzopyrazolyl or benzo % Azole-based compound 'wherein B is an ethylidene compound in the following formula, (XV) -cr

YH 其中YH where

Ra，A及Y之定義如申請專利範圍第1至8項所述’與如 下通式之化合物反應. HO - CO - CH2CH2 - Ar - E , (XVI) 其中 A r及E之定義如申請專利範圍第1至8項所述，或與其 易反應的衍生物反應，及 i ·要製備通式之喳喏啉-2 -酮化合物時， 用如下通式之化合物 ，（XVI!> NR, Η -13-本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 8 5The definitions of Ra, A, and Y are as described in Items 1 to 8 of the scope of the patent application. 'React with compounds of the following formula. HO-CO-CH2CH2-Ar-E, (XVI) where A r and E are defined as in the patent application As described in the items 1 to 8 of the range, or reacting with its easily-reactive derivative, and i. To prepare a fluorin-2-one compound of the general formula, use a compound of the following formula, (XVI! ≫ NR, Η -13- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 8 5

具中Guzhong

Ra，Rl及A之定義如申請專利範圍第項所述，1 如下通式之化合物反應， H〇-C〇.C〇CH2- Ar.E ，（XVlH) 其中 ，或與The definitions of Ra, Rl, and A are as described in the first item of the scope of the patent application. 1 reacts with a compound of the general formula, H0-C0.C0CH2-Ar.E, (XVlH) where, or

Ar及E之定義如申請專利範圍第丨至8項所述 易反應的衍生物反應，或 綠基 j·要製備通式I之化合物，其中R2是經以燒基磺 基羰基取代的C ! y燒基，時 以如下通式之化合物 ，（IXX)The definitions of Ar and E are as described in the easily-reactable derivative reaction described in the scope of application patent Nos. 丨 8, or green group j. To prepare a compound of general formula I, where R2 is C substituted with a sulfocarbonyl group! y-alkyl, when it is a compound of the following formula, (IXX)

N - A - Het - B - Ar - E 其中 R3，A，B，E，及net之定義如申請專利範圍第i至8 所述，R2’是經羧基取代的^广烷基，或其易反應的 生物，與如下通式.化合物的鹽反應N-A-Het-B-Ar-E where R3, A, B, E, and net are defined as described in claims i to 8 of the patent application range, and R2 'is a carboxyl-substituted alkyl group, or Reacting organisms, react with salts of compounds of the following formula.

Ci.3 .烷基 _ s〇2 - NH2 (XX)· 並且，如有必要，裂解反應中用以保護易反應的基團 保護基及/或 將所製通式Z化合物轉化成其鹽，特別是用無機或有 酸或鹼轉化成其供醫藥用途的生理上可接受的鹽。 -14-Ci.3. Alkyl_s〇2-NH2 (XX), and, if necessary, protecting the reactive group protecting group in the cleavage reaction and / or converting the compound of the general formula Z into its salt, In particular, it is converted with an inorganic or acid or base into a physiologically acceptable salt thereof for medical use. -14-

TW087102265A 1997-02-18 1998-02-18 Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions TW588047B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19706229A DE19706229A1 (en) 1997-02-18 1997-02-18 New aryl-substituted bi:cyclic heterocyclic compounds
DE1997151939 DE19751939A1 (en) 1997-11-24 1997-11-24 New aryl-substituted bi:cyclic heterocyclic compounds

Publications (1)

Publication Number Publication Date
TW588047B true TW588047B (en) 2004-05-21

Family

ID=26034058

Family Applications (1)

Application Number Title Priority Date Filing Date
TW087102265A TW588047B (en) 1997-02-18 1998-02-18 Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions

Country Status (39)

Country Link
EP (1) EP0966454B1 (en)
JP (1) JP3343359B2 (en)
KR (1) KR100619458B1 (en)
CN (1) CN1088702C (en)
AR (1) AR010896A1 (en)
AT (1) ATE239712T1 (en)
AU (1) AU742593C (en)
BG (1) BG64558B1 (en)
BR (1) BR9807843B1 (en)
CA (1) CA2277949C (en)
CO (1) CO4920237A1 (en)
CZ (1) CZ297768B6 (en)
DE (2) DE59808281D1 (en)
DK (1) DK0966454T3 (en)
EA (1) EA003697B1 (en)
EE (1) EE04716B1 (en)
EG (1) EG24144A (en)
ES (1) ES2199426T4 (en)
FR (1) FR08C0025I2 (en)
HK (1) HK1025096A1 (en)
HR (1) HRP980082B1 (en)
HU (1) HU223754B1 (en)
IL (1) IL130812A (en)
LT (1) LTC0966454I2 (en)
LU (1) LU91437I2 (en)
MY (1) MY129408A (en)
NL (1) NL300349I2 (en)
NO (3) NO313879B1 (en)
NZ (1) NZ337323A (en)
PE (1) PE121699A1 (en)
PL (1) PL195551B1 (en)
PT (1) PT966454E (en)
RS (1) RS49686B (en)
SA (1) SA98190047B1 (en)
SI (1) SI0966454T1 (en)
SK (1) SK285432B6 (en)
TR (1) TR199902017T2 (en)
TW (1) TW588047B (en)
WO (1) WO1998037075A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI391382B (en) * 2005-12-21 2013-04-01 Boehringer Ingelheim Int Improved process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof

Families Citing this family (170)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1608399A (en) * 1997-11-26 1999-06-15 Axys Pharmaceuticals, Inc. Substituted amidinoaryl derivatives and their use as anticoagulants
US6114532A (en) * 1998-02-03 2000-09-05 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, the preparation thereof, and their use as pharmaceuticals
WO1999040072A1 (en) * 1998-02-03 1999-08-12 Boehringer Ingelheim Pharma Kg Five-membered, benzo-condensed heterocycles used as antithrombotic agents
NZ506507A (en) * 1998-02-09 2003-08-29 Dimensional Pharm Inc Heteroaryl amidine, methylamidine or guanidine derivatives useful as urokinase inhibitors
US6291514B1 (en) 1998-02-09 2001-09-18 3-Dimensional Pharmaceuticals, Inc. Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors
TWI248435B (en) * 1998-07-04 2006-02-01 Boehringer Ingelheim Pharma Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions
US6248770B1 (en) 1998-07-09 2001-06-19 Boehringer Ingelheim Pharma Kg Benzimidazoles having antithrombotic activity
BR9917036A (en) * 1999-02-09 2002-07-30 Dimensional Pharm Inc Heteroaryl amidines, methylamidines and guanidines as protease inhibitors
DE19907813A1 (en) * 1999-02-24 2000-08-31 Boehringer Ingelheim Pharma Substituted bicyclic heterocycles, their preparation and their use as pharmaceuticals
AR023510A1 (en) 1999-04-21 2002-09-04 Astrazeneca Ab A TEAM OF PARTS, PHARMACEUTICAL FORMULATION AND USE OF A THROMBIN INHIBITOR.
US6512000B1 (en) 1999-08-20 2003-01-28 Boehringer Ingelheim Pharma Kg Aminocarbonyl-substituted benzimidazoles having tryptase-inhibitory activity
DE19939463A1 (en) * 1999-08-20 2001-02-22 Boehringer Ingelheim Pharma Tryptase inhibitors useful e.g. for treating inflammatory or allergic disease, arteriosclerosis or neoplasia, comprising new or known 2-phenethyl-benzimidazole-5-carboxamides
DE50001742D1 (en) * 1999-09-24 2003-05-15 Boehringer Ingelheim Pharma ARYLSULFONAMIDE SUBSTITUTED BENZIMIDAZOLE DERIVATIVES AND THEIR USE AS TRYPTASE INHIBITORS
DE19945787A1 (en) 1999-09-24 2001-03-29 Boehringer Ingelheim Pharma New 2-(amidino- or aminomethyl-phenethyl)-5-sulfonylamino-benzimidazoles, are tryptase inhibitors useful e.g. for treating inflammatory or allergic disease such as asthma, urticaria or arthritis
DE19945810A1 (en) * 1999-09-24 2001-03-29 Boehringer Ingelheim Pharma Substituted benzimidazole derivatives, process for their preparation and their use as medicaments
US6413990B1 (en) 1999-09-24 2002-07-02 Boehringer Ingelheim Pharma Kg Arylsulphonamide-substituted benzimidazoles having tryptase-inhibiting activity
US6407130B1 (en) 1999-11-10 2002-06-18 Boehringer Ingelheim Pharma Kg Carboxamide-substituted benzimidazoles having tryptase-inhibiting activity
US6451832B2 (en) 1999-12-23 2002-09-17 Boehringer Ingelheim Pharma Kg Benzimidazoles with antithrombotic activity
US6448281B1 (en) * 2000-07-06 2002-09-10 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
CN1243735C (en) * 2001-04-19 2006-03-01 卫材株式会社 2-lminopyrrolidine derivatives
DE10133786A1 (en) * 2001-07-16 2003-02-06 Boehringer Ingelheim Pharma Use of thrombin inhibitors for the treatment of arthritis
US20030181488A1 (en) * 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
PT1870100E (en) * 2002-03-07 2012-04-17 Boehringer Ingelheim Int Ethyl 3-(2-(4-(hexyloxycarbonylamidino)phenylaminomethyl)-1-methyl-1h-benzimidazole-5-carbonyl)-2-pyridylamino)propionate methansulfonate
DE10235639A1 (en) * 2002-08-02 2004-02-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg New prodrugs of benzimidazole-5-carboxamide derivative thrombin inhibitor, useful for treating or preventing thrombotic diseases, are well tolerated on subcutaneous injection
AU2003265398A1 (en) 2002-08-09 2004-02-25 Transtech Pharma, Inc. Aryl and heteroaryl compounds and methods to modulate coagulation
PE20040804A1 (en) 2002-12-19 2004-12-31 Boehringer Ingelheim Pharma CARBOXAMID DERIVATIVES AS INHIBITORS OF THE Xa FACTOR
DE10260730A1 (en) * 2002-12-23 2004-07-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel substituted nitrogen-containing heterobicyclene, their preparation and their use as pharmaceuticals
US7429597B2 (en) 2002-12-23 2008-09-30 Boehringer Ingelheim Pharma Gmbh & Co., Kg Substituted nitrogen-containing heterobicycles, the preparation thereof and their use as pharmaceutical compositions
EP2444393A1 (en) 2003-02-19 2012-04-25 Eisai R&D Management Co., Ltd. Methods for producing cyclic benzamidine derivatives
DE10310278A1 (en) * 2003-03-10 2004-09-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg New N-(benzazinyl)-(hetero)aralkylamine derivatives, are inhibitors of factor Xa and/or related serine proteases, useful e.g. as antithrombotic agents and intermediates
RU2005136383A (en) 2003-04-24 2007-06-10 БЕРИНГЕР ИНГЕЛЬХАЙМ ИНТЕРНАЦИОНАЛЬ ГмбХ (DE) APPLICATION OF DIPYRIDAMOL OR MOPIDAMOL FOR TREATMENT AND PREVENTION OF THROMBOEMBOLIC DISEASES AND DISORDERS CAUSED BY REDUCED EDUCATION AND / OR HIGH LEVEL OF EXPRESSION OF TROMBRINES
CN1832920A (en) * 2003-08-08 2006-09-13 特兰斯泰克制药公司 Aryl and heteroaryl compounds, compositions, and methods of use
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use
US7501538B2 (en) 2003-08-08 2009-03-10 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions and methods of use
DE10337697A1 (en) * 2003-08-16 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tablet containing 3 - [(2 - {[4- (hexyloxycarbonylamino-iminomethyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] - propionic acid ethyl ester or its salts
DE10339862A1 (en) * 2003-08-29 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg New crystalline forms of ethyl 3-(N-(2-(4-(hexyloxycarbonylamidino)phenylaminomethyl)-1-methyl-1H-benzimidazole-5-carbonyl)-N-(2-pyridyl)amino)propionate methanesulfonate used for post-operative prophylaxis of deep vein thrombosis
DE10341043A1 (en) * 2003-09-03 2005-03-31 Boehringer Ingelheim Pharma Gmbh & Co. Kg New Oral Dosage Form for 3 - [(2 - {[4-hexyloxycarbonylamino-imino-methyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] Propionic acid ethyl ester and its salts
EP1609784A1 (en) * 2004-06-25 2005-12-28 Boehringer Ingelheim Pharma GmbH & Co.KG Process for the preparation of 4-(benzimidazolylmethylamino)-benzamidines
US20060222640A1 (en) * 2005-03-29 2006-10-05 Boehringer Ingelheim International Gmbh New pharmaceutical compositions for treatment of thrombosis
DE102005020002A1 (en) * 2005-04-27 2006-11-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg New hexyloxycarbonylamino-imino-methyl-phenylamino-methyl-benzimidazole-pyridine-propionic acid-ethyl ester salts such as hydrochloride useful for the prophylaxis of vein thrombosis and stroke
DE102005025728A1 (en) * 2005-06-04 2006-12-07 Boehringer Ingelheim Pharma Gmbh & Co. Kg Polymorphs of 3 - [(2 - {[4- (hexyloxycarbonylamino-imino-methyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] -propionic acid ethyl ester
WO2007002635A2 (en) 2005-06-27 2007-01-04 Bristol-Myers Squibb Company C-linked cyclic antagonists of p2y1 receptor useful in the treatment of thrombotic conditions
DE102005061624A1 (en) * 2005-12-21 2007-06-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Improved process for the preparation of salts of 4- (benzimidazolylmethylamino) -benzamidines
WO2007103996A1 (en) 2006-03-09 2007-09-13 Bristol-Myers Squibb Company 2-(aryloxy)acetamide factor viia inhibitors useful as anticoagulants
EP2061756B1 (en) 2006-06-08 2013-09-25 Bristol-Myers Squibb Company 2-aminocarbonylphenylamino-2-phenilacetamides as factor viia inhibitors useful as anticoagulants
CA2657269A1 (en) * 2006-07-17 2008-01-24 Boehringer Ingelheim International Gmbh New indications for direct thrombin inhibitors
CL2007002068A1 (en) * 2006-07-17 2008-01-18 Boehringer Ingelheim Int Use of dabigatran, dabigatran ethoxylate, (n-2-pyridyl-n-2-ethoxycarbonylethyl) amide of 1-methyl-2- [4- (n-hydroxyamidino) phenylaminoethyl] benzimidazol-5-yl-carboxylic acid, melagatran, ximelagatran, hirudin, hirulog and argatroban for the treatment of cerebral infarction, myocardial infarction, thrombosis, pulmonary embolism, among others.
US20100087488A1 (en) * 2006-10-10 2010-04-08 Boehringer Ingelheim International Gmgh Physiologically Acceptable Salts of 3-[(2--1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester
JP5342450B2 (en) 2006-12-15 2013-11-13 ブリストル−マイヤーズ スクイブ カンパニー Arylpropionamide, arylacrylamide, arylpropinamide, or arylmethylurea analogs as factor XIa inhibitors
PE20081775A1 (en) 2006-12-20 2008-12-18 Bristol Myers Squibb Co MACROCYCLIC COMPOUNDS AS INHIBITORS OF FACTOR VIIA
EP1956018A1 (en) * 2007-02-06 2008-08-13 Boehringer Ingelheim Pharma GmbH & Co. KG Method of preparing a derivative of benzimidazole
BRPI0810462A2 (en) 2007-04-23 2014-10-14 Sanofi Aventis KINOLIN-CARBOXAMIDE DERIVATIVES AS P2Y12 ANTAGONISTS
EP2178849A1 (en) 2007-07-31 2010-04-28 Mallinckrodt Inc. Integrated photoactive agents and uses thereof
EP2238128B1 (en) 2007-12-26 2012-08-22 Sanofi Heterocyclic pyrazole-carboxamides as p2y12 antagonists
CZ305085B6 (en) * 2008-03-14 2015-04-29 Zentiva, K.S. Process for preparing dabigatran
NZ589746A (en) 2008-07-14 2012-10-26 Boehringer Ingelheim Int Method for manufacturing medicinal compounds containing dabigatran
EP2328581A1 (en) * 2008-08-19 2011-06-08 Boehringer Ingelheim International GmbH Use of dabigatranetexilate for treating patients with pulmonary hypertension
CZ2008669A3 (en) * 2008-10-24 2010-05-05 Zentiva, A. S. Process for preparing dabigatran and intermediates thereof
NZ593787A (en) * 2009-02-02 2013-09-27 Boehringer Ingelheim Int Lyophilised dabigatran
WO2010130757A1 (en) 2009-05-14 2010-11-18 Boehringer Ingelheim International Gmbh New combination therapy in treatment of oncological and fibrotic diseases
CN102481317B (en) 2009-08-24 2014-09-03 贝林格尔.英格海姆国际有限公司 Emergency interventions of active charcoal with dabigatran etexilate overdosing
CN102050814B (en) * 2009-11-06 2014-05-28 北京美倍他药物研究有限公司 Ester derivatives of dabigatran
CN102050815B (en) * 2009-11-06 2014-04-02 北京美倍他药物研究有限公司 Dabigatran ester derivatives as prodrug
US8399678B2 (en) * 2009-11-18 2013-03-19 Boehringer Ingelheim International Gmbh Process for the manufacture of dabigatran etexilate
AR079944A1 (en) 2010-01-20 2012-02-29 Boehringer Ingelheim Int NEUTRALIZING ANTIBODY OF THE ACTIVITY OF AN ANTICOAGULANT
HUP1000069A2 (en) 2010-02-02 2012-05-02 Egis Gyogyszergyar Nyilvanosan M Kod Ruszvunytarsasag New salts for the preparation of pharmaceutical composition
EP3786165A1 (en) 2010-02-11 2021-03-03 Bristol-Myers Squibb Company Synthetic intermediates for producing macrocycles as factor xia inhibitors
SI2542224T1 (en) 2010-03-01 2014-10-30 Ratiopharm Gmbh Dabigatran etexilate-containing oral pharmaceutical composition
JP2013521318A (en) 2010-03-08 2013-06-10 ラティオファルム ゲー・エム・ベー・ハー Pharmaceutical composition containing dabigatran etexilate
PT2588090T (en) 2010-07-01 2017-06-26 Krka Tovarna Zdravil D D Novo Mesto Pharmaceutical oral dosage forms comprising dabigatran etexilate and its pharmaceutically acceptable salts
MX2013000295A (en) 2010-07-09 2013-05-28 Esteve Quimica Sa Process of preparing a thrombin specific inhibitor.
JP2013531004A (en) 2010-07-09 2013-08-01 エステヴェ キミカ， エス．エー． Intermediates and methods for the preparation of thrombin specific inhibitors
WO2012027543A1 (en) 2010-08-25 2012-03-01 Teva Pharmaceuticals Usa, Inc. Solid state forms of dabigatran etexilate, dabigatran etexilate mesylate and processes for preparation thereof
EP2649060B1 (en) 2010-12-06 2017-04-05 MSN Laboratories Limited Process for the preparation of benzimidazole derivatives and its salts
EP2671582B1 (en) 2011-02-01 2016-07-13 Kyowa Hakko Kirin Co., Ltd. Ring-fused heterocyclic derivative
EP2691156A1 (en) 2011-03-30 2014-02-05 Boehringer Ingelheim International GmbH Anticoagulant antidotes
HUP1100244A2 (en) 2011-05-11 2012-11-28 Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag Pharmaceutical intermediates and process for their production
CN102250099B (en) * 2011-05-16 2013-10-16 中国药科大学 Non-peptide thrombin inhibitors as well as preparation method and medical application thereof
CN102838588B (en) * 2011-06-24 2014-03-19 中国药科大学 Oral thrombin inhibitors, preparation methods and medical uses thereof
EP2550966B1 (en) * 2011-07-25 2016-10-19 Dritte Patentportfolio Beteiligungsgesellschaft mbH & Co. KG Amidoxime carboxylic acid esters of dabigatran as prodrugs and their use as medicament
TW201311689A (en) 2011-08-05 2013-03-16 必治妥美雅史谷比公司 Novel macrocycles as factor XIa inhibitors
TW201319068A (en) 2011-08-05 2013-05-16 必治妥美雅史谷比公司 Cyclic P1 linkers as factor XIa inhibitors
WO2013024394A1 (en) * 2011-08-12 2013-02-21 Alembic Pharmaceuticals Limited Novel reference markers of dabigatran etexilate
CN102993174A (en) * 2011-09-08 2013-03-27 天津药物研究院 Dabigatran etexilate derivative as a prodrug
CN102993175B (en) * 2011-09-08 2014-08-13 天津药物研究院 Dabigatran derivatives, and preparation method and application thereof
ES2699226T3 (en) 2011-10-14 2019-02-08 Bristol Myers Squibb Co Substituted tetrahydroisoquinoline compounds as inhibitors of factor XIa
ES2579832T3 (en) 2011-10-14 2016-08-17 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors
CA2851810C (en) 2011-10-14 2020-01-07 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor xia inhibitors
MX2014007331A (en) 2011-12-22 2014-09-01 Boehringer Ingelheim Int Immediate release multi unit pellet system.
WO2013111163A2 (en) 2012-01-20 2013-08-01 Cadila Healthcare Limited Process for the preparation of dabigatran etexilate mesylate and polymorphs of intermediates thereof
JP2015504903A (en) 2012-01-24 2015-02-16 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング New dabigatran formulation for oral administration
ES2895918T3 (en) 2012-02-21 2022-02-23 Towa Pharmaceutical Europe S L Dabigatran etexilate oral pharmaceutical compositions
EP2631234A1 (en) 2012-02-23 2013-08-28 Esteve Química, S.A. Solid forms of dabigatran etexilate mesylate and processes for their preparation
WO2013144971A1 (en) 2012-03-27 2013-10-03 Cadila Healthcare Limited New solid forms of dabigatran etexilate bisulfate and mesylate and processes to prepare them
US9273030B2 (en) 2012-04-02 2016-03-01 Msn Laboratories Private Limited Process for the preparation of benzimidazole derivatives and salts thereof
CN103387566B (en) * 2012-05-09 2015-09-09 上海医药工业研究院 Prepare the method for 3-[[[2-[[(4-cyano-phenyl) is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate
CN103420980A (en) * 2012-05-22 2013-12-04 北京美倍他药物研究有限公司 Dabigatran derivatives
US20130345262A1 (en) 2012-06-25 2013-12-26 Boehringer Ingelheim International Gmbh Method for prevention of stroke
EP2872499A1 (en) 2012-07-16 2015-05-20 Interquim, S.A. Process for the preparation of intermediates for the synthesis of dabigatran etexilate, and crystalline forms of said intermediates
CN102766134B (en) * 2012-07-19 2014-06-25 北京普禄德医药科技有限公司 Dabigatran etexilate derivative and preparation method and application thereof
EP2881394B1 (en) * 2012-07-31 2018-03-21 Kyowa Hakko Kirin Co., Ltd. Condensed ring heterocyclic compound
EA028581B1 (en) 2012-08-03 2017-12-29 Бристол-Маерс Сквибб Компани DIHYDROPYRIDONE P1 AS FACTOR XIa INHIBITORS
EA025392B1 (en) 2012-08-03 2016-12-30 Бристол-Маерс Сквибб Компани DIHYDROPYRIDONE P1 AS FACTOR XIa INHIBITORS
WO2014041559A2 (en) * 2012-08-27 2014-03-20 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for the preparation of dabigatran etexilate and intermediates thereof
WO2014060561A1 (en) 2012-10-19 2014-04-24 Sanovel Ilac Sanayi Ve Ticaret A.S. Oral pharmaceutical formulations comprising dabigatran
WO2014060545A1 (en) 2012-10-19 2014-04-24 Sanovel Ilac Sanayi Ve Ticaret A.S. Pharmaceutical compositions of dabigatran free base
US9399616B2 (en) 2012-10-22 2016-07-26 Boehringer Ingelheim International Gmbh Process for the manufacture of 4-aminobenzoamidine dihydrochloride
US10077251B2 (en) 2012-10-29 2018-09-18 Biophore India Pharmaceuticals Pvt. Ltd. Process for the synthesis of Dabigatran Etexilate and its intermediates
US9533971B2 (en) 2012-10-29 2017-01-03 Biophore India Pharmaceuticals Pvt. Ltd Process for the synthesis of dabigatran and its intermediates
CN102977077A (en) * 2012-11-28 2013-03-20 浙江燎原药业有限公司 Method for preparing dabigatran etexilate intermediate
EP2740471B1 (en) 2012-12-07 2015-05-27 Hexal AG Oral pharmaceutical composition comprising dabigatran etexilate
CN103044404A (en) * 2013-01-14 2013-04-17 中国药科大学 Dabigatran derivatives, and preparation method and application thereof in antithrombosis
WO2014160668A1 (en) 2013-03-25 2014-10-02 Bristol-Myers Squibb Company Tetrahydroisoquinolines containing substituted azoles as factor xia inhibitors
CN103224469A (en) * 2013-05-16 2013-07-31 上海应用技术学院 Pradaxa analogue with fluorine-containing group modified benzene ring as center and synthesis method thereof
EP3004086A1 (en) 2013-06-03 2016-04-13 Bayer Pharma Aktiengesellschaft Substituted benzoxazoles
UY35592A (en) 2013-06-03 2014-12-31 Bayer Pharma AG BENZOXAZOLES REPLACED
CN103288744A (en) * 2013-06-04 2013-09-11 上海应用技术学院 Fluorine group-containing-modified dabigatran etexilate analogue and synthetic method thereof
EP2853260A1 (en) 2013-09-27 2015-04-01 ratiopharm GmbH Pharmaceutical preparation comprising dabigatran etexilate bismesylate
NO2760821T3 (en) 2014-01-31 2018-03-10
RS57659B1 (en) 2014-01-31 2018-11-30 Bristol Myers Squibb Co Macrocycles with hetrocyclic p2' groups as factor xia inhibitors
WO2015128875A2 (en) 2014-02-26 2015-09-03 Megafine Pharma (P) Ltd. A process for preparation of dabigatran etexilate mesylate and intermediates thereof
WO2015137680A1 (en) * 2014-03-10 2015-09-17 동아에스티 주식회사 Pharmaceutical composition for treating or preventing stroke and systemic embolism
IN2014MU01042A (en) 2014-03-26 2015-10-02 Cadila Healthcare Ltd
EP2929884A1 (en) 2014-04-11 2015-10-14 Sanovel Ilac Sanayi ve Ticaret A.S. Pharmaceutical combinations of dabigatran and h2-receptor antagonists
US10130618B2 (en) 2014-04-11 2018-11-20 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Pharmaceutical combinations of dabigatran and proton pump inhibitors
CN104230888A (en) * 2014-06-03 2014-12-24 长春工业大学 Preparation method of benzimidazole compound
CN105218519A (en) * 2014-06-04 2016-01-06 天津药物研究院 A kind of preparation method of dabigatran etexilate intermediate
CN104003977B (en) * 2014-06-05 2016-04-13 雅本化学股份有限公司 The preparation method of N-(2-chloromethyl-1-methyl isophthalic acid H-benzoglyoxaline-5-acyl group)-N-(pyridine-2-base)-3-alanine ethyl ester
DE102014108210A1 (en) 2014-06-11 2015-12-17 Dietrich Gulba rodenticide
CN104045628B (en) * 2014-06-13 2019-04-09 深圳翰宇药业股份有限公司 The purification process of benzimidizole derivatives
CN105315257A (en) * 2014-06-24 2016-02-10 华仁药业股份有限公司 Synthetic and purifying method of dabigatran etexilate
CN107027308A (en) * 2014-08-06 2017-08-08 四川海思科制药有限公司 A kind of dabigatran thioes derivatives and preparation method thereof and purposes pharmaceutically
WO2016019849A1 (en) * 2014-08-06 2016-02-11 四川海思科制药有限公司 Dabigatran carboalkoxy derivative, preparation method therefor, and pharmaceutical use thereof
NO2721243T3 (en) 2014-10-01 2018-10-20
CA3001495C (en) 2014-11-03 2021-07-20 Solipharma Llc Formulations of dabigatran etexilate or dabigatran etexilate salts and preparation methods thereof
CN104592204B (en) * 2014-12-26 2017-05-17 华润赛科药业有限责任公司 Dabigatran derivatives as well as preparation method and application thereof
CN104650037A (en) * 2014-12-30 2015-05-27 青岛黄海制药有限责任公司 Synthesis method of dabigatran etexilate
TR201502223A2 (en) 2015-02-25 2016-09-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Pharmaceutical combinations of dronedarone and dabigatran
CN104628733A (en) * 2015-03-02 2015-05-20 中国药科大学 Tetrahydrobenzo[4,5] imidazo[1,2-a] pyrazine thrombin inhibitors
US10160750B2 (en) 2015-06-19 2018-12-25 Bristol-Myers Squibb Company Diamide macrocycles as factor XIa inhibitors
CN104987323B (en) * 2015-07-10 2017-08-22 浙江美诺华药物化学有限公司 A kind of preparation method of dabigatran etcxilate
EP3324946A1 (en) 2015-07-20 2018-05-30 Sanovel Ilac Sanayi ve Ticaret A.S. Pharmaceutical formulations of dabigatran free base
WO2017019821A1 (en) 2015-07-29 2017-02-02 Bristol-Myers Squibb Company Factor xia new macrocycle bearing a non-aromatic p2' group
EP3331872B1 (en) 2015-08-05 2019-09-25 Bristol-Myers Squibb Company Novel substituted glycine derived fxia inhibitors
CN105294651A (en) * 2015-09-23 2016-02-03 烟台东诚药业集团股份有限公司 Method for synthesizing and preparing pradaxa formamidine intermediates
CN106866626A (en) * 2015-12-14 2017-06-20 天津药物研究院有限公司 A kind of preparation method of dabigatran etexilate intermediate
CN105481831B (en) * 2015-12-16 2018-06-12 开封明仁药业有限公司 A kind of method for preparing dabigatran etexilate intermediate
WO2017111637A1 (en) 2015-12-23 2017-06-29 Zaklady Farmaceutyczne Polpharma Sa Pharmaceutical composition comprising dabigatran or a pharmaceutically acceptable salt thereof
CN105566297A (en) * 2015-12-31 2016-05-11 哈药集团技术中心 Preparation method of dabigatran etexilate mesylate
KR20180117156A (en) 2016-03-02 2018-10-26 브리스톨-마이어스 스큅 컴퍼니 Diamide macrocycle with factor XIa inhibitory activity
CN105669651B (en) * 2016-03-07 2018-03-06 山东罗欣药业集团股份有限公司 A kind of preparation technology of dabigatran etexilate methanesulfonate
CN106397400A (en) * 2016-04-14 2017-02-15 江苏康缘药业股份有限公司 Preparation method for dabigatran etexilate
TR201606697A2 (en) 2016-05-20 2017-12-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi NEW ORAL PHARMACEUTICAL FORMULATIONS OF DABIGATRA
CN106349221A (en) * 2016-08-29 2017-01-25 常州市阳光药业有限公司 Preparation method of high-purity dabigatran etexilate
TR201617984A2 (en) 2016-12-07 2018-06-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi PHARMACEUTICAL COMPOSITIONS OF DABIGATRAN
EP3332771A1 (en) 2016-12-07 2018-06-13 Sanovel Ilac Sanayi ve Ticaret A.S. Multilayered tablet compositions of dabigatran
JP2018184375A (en) 2017-04-27 2018-11-22 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Tablet comprising dabigatran etexilate or pharmaceutically acceptable salt thereof and method for producing the same
WO2019004980A2 (en) 2017-05-10 2019-01-03 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Solid oral pharmaceutical compositions of dabigatran etexilate
TR201706848A2 (en) 2017-05-10 2018-11-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi SOLID ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING DABIGATRAN ETEXCLATE
CN109010249A (en) * 2017-06-08 2018-12-18 上海美悦生物科技发展有限公司 Injection dabigatran etcxilate pharmaceutical composition and its preparation method and application
KR20190036857A (en) 2017-09-28 2019-04-05 한미약품 주식회사 Composite capsule formulation comprising dabigatran etexilate
TR201722323A2 (en) 2017-12-27 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Oral pharmaceutical compositions of dabigatran
TR201722186A2 (en) 2017-12-27 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Pharmaceutical compositions of dabigatran
TR201722630A2 (en) 2017-12-28 2019-07-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
CN111954532A (en) * 2018-04-13 2020-11-17 上海交通大学医学院附属瑞金医院 Anti-tumor multi-drug resistance of heteroaryl amide compounds, application of heteroaryl amide compounds in treating cancer and protein-drug molecular compound
CN108864047A (en) * 2018-07-02 2018-11-23 河南师范大学 A kind of preparation method of non-peptide batroxobin inhibitor dabigatran etcxilate
EP3771465A1 (en) 2019-08-01 2021-02-03 Zaklady Farmaceutyczne Polpharma SA Pharmaceutical composition comprising dabigatran etexilate
CN111606885A (en) * 2020-06-18 2020-09-01 安徽鼎旺医药有限公司 Dabigatran etexilate mesylate and preparation method thereof
CN113929661A (en) * 2020-06-29 2022-01-14 石药集团恩必普药业有限公司 Dabigatran etexilate intermediate and preparation method thereof
EP4070658A1 (en) 2021-04-06 2022-10-12 BIORoxx GmbH Use of anticoagulant active compounds as rodenticide

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4675405A (en) * 1984-09-21 1987-06-23 American Home Products Corporation Quinoline compounds as antiallergic and antithrombotic agents
DE4129603A1 (en) * 1991-09-06 1993-03-11 Thomae Gmbh Dr K CONDENSED 5-LOW HETEROCYCLES, METHOD FOR THE PRODUCTION THEREOF, AND MEDICAMENTS CONTAINING THESE COMPOUNDS
US5416099A (en) * 1991-10-29 1995-05-16 Merck & Co., Inc. Fibrinogen receptor antagonists
ZA928276B (en) * 1991-10-31 1993-05-06 Daiichi Seiyaku Co Aromatic amidine derivates and salts thereof.
CA2134192A1 (en) * 1993-11-12 1995-05-13 Michael L. Denney 5, 6-bicyclic glycoprotein iib/iiia antagonists

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI391382B (en) * 2005-12-21 2013-04-01 Boehringer Ingelheim Int Improved process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof

Also Published As

Publication number Publication date
EP0966454A1 (en) 1999-12-29
PL195551B1 (en) 2007-10-31
EG24144A (en) 2008-08-06
AU742593C (en) 2004-04-29
NO2008012I1 (en) 2008-08-25
IL130812A (en) 2005-12-18
HUP0001116A2 (en) 2001-05-28
FR08C0025I2 (en) 2009-11-20
ATE239712T1 (en) 2003-05-15
EE9900359A (en) 2000-02-15
JP2001509815A (en) 2001-07-24
HK1025096A1 (en) 2000-11-03
DE122008000020I1 (en) 2008-08-07
EA199900746A1 (en) 2000-08-28
AU6399198A (en) 1998-09-09
CZ297768B6 (en) 2007-03-28
HU223754B1 (en) 2005-01-28
NO313879B1 (en) 2002-12-16
LU91437I9 (en) 2019-01-02
ES2199426T4 (en) 2007-08-16
NO993945L (en) 1999-10-15
KR100619458B1 (en) 2006-09-08
HUP0001116A3 (en) 2001-07-30
LTPA2008008I1 (en) 2021-02-25
EP0966454B1 (en) 2003-05-07
EA003697B1 (en) 2003-08-28
RS49686B (en) 2007-12-31
CN1088702C (en) 2002-08-07
NO2021005I1 (en) 2021-02-05
PT966454E (en) 2003-09-30
DK0966454T3 (en) 2003-09-01
DE59808281D1 (en) 2003-06-12
NO2008012I2 (en) 2010-05-25
AU742593B2 (en) 2002-01-10
BR9807843B1 (en) 2010-06-29
ES2199426T3 (en) 2004-02-16
BG103655A (en) 2000-02-29
SI0966454T1 (en) 2003-10-31
PE121699A1 (en) 1999-12-08
CO4920237A1 (en) 2000-05-29
TR199902017T2 (en) 1999-10-21
CN1248251A (en) 2000-03-22
PL335154A1 (en) 2000-04-10
CA2277949C (en) 2006-10-03
SK112199A3 (en) 2000-05-16
LTC0966454I2 (en) 2021-08-10
KR20000071066A (en) 2000-11-25
AR010896A1 (en) 2000-07-12
CA2277949A1 (en) 1998-08-27
EE04716B1 (en) 2006-10-16
IL130812A0 (en) 2001-01-28
NL300349I2 (en) 2008-10-01
NO993945D0 (en) 1999-08-17
CZ291599A3 (en) 2000-06-14
NL300349I1 (en) 2008-08-01
JP3343359B2 (en) 2002-11-11
WO1998037075A1 (en) 1998-08-27
YU38799A (en) 2001-03-07
BG64558B1 (en) 2005-07-29
HRP980082B1 (en) 2003-08-31
MY129408A (en) 2007-03-30
BR9807843A (en) 2001-06-19
LU91437I2 (en) 2008-07-14
SK285432B6 (en) 2007-01-04
HRP980082A2 (en) 1998-10-31
FR08C0025I1 (en) 2008-07-18
SA98190047B1 (en) 2005-12-12
NZ337323A (en) 2000-11-24

Similar Documents

Publication Publication Date Title
TW588047B (en) Disubstituted bicyclic heterocycles, the preparation and the use thereof as pharmaceutical compositions
US6414008B1 (en) Disubstituted bicyclic heterocycles, the preparation thereof, and their use as pharmaceutical compositions
US6710055B2 (en) Disubstituted bicyclic heterocycles, the preparation thereof, and their use as pharmaceutical compositions
RU1836357C (en) Benzimidazole derivatives, their isomers, mixtures of isomers, hydrates or their physiologically bearable salts possessing properties antagonistic to angiotenzine
US7576114B2 (en) N3 alkylated benzimidazole derivatives as MEK inhibitors
US7842816B2 (en) N3 alkylated benzimidazole derivatives as MEK inhibitors
HRP940752A2 (en) Benzimidazol, medicaments containing them and process for their preparation
AU2008242488B2 (en) Benzimidazoles and pharmaceutical compositions thereof
JP2002502844A (en) 5-membered heterocyclic fused benzo derivatives, their preparation and their use as pharmaceuticals
JPH05221999A (en) Five-membered heterocyclic compound, prepara- tion thereof and pharmaceutical composition containing this compound
ZA200108609B (en) Heterocyclically substituted benzimidazoles, the production and application thereof.
KR20080077655A (en) Pdf inhibitors
KR20010083087A (en) Benzimidazoles, production thereof and use thereof as medicaments
JP2012507525A5 (en)
WO2009061730A2 (en) 4-heteroaryl-substituted phenoxyphenylacetic acid
CA2089689A1 (en) Substituted biphenylyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them
SK32493A3 (en) Benzimidazole derivatives, process for their preparation and pharmaceutical compositions with their contents
JPH05279341A (en) Benzimidazoles, medicinal composition containing these compound and their preparation
JPH0649038A (en) Substituted benzoimidazolyl derivative, medicine composition containing same, and its preparation
SK106693A3 (en) Benzimidazole derivatives, process of their production and pharmaceutical agents with the content of those
CA2402686C (en) Vitronectin receptor antagonist bicyclic compounds, preparation method and compositions containing same
US7371769B2 (en) Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-D2 receptors and serotonin reuptake sites

Legal Events

Date Code Title Description
MK4A Expiration of patent term of an invention patent